title: A weighted genetic risk score using all known susceptibility variants to estimate rheumatoid arthritis risk.
abstract: BACKGROUND
  There is currently great interest in the incorporation of genetic susceptibility loci into screening models to identify individuals at high risk of disease. Here, we present the first risk prediction model including all 46 known genetic loci associated with rheumatoid arthritis (RA).
  
  
  METHODS
  A weighted genetic risk score (wGRS) was created using 45 RA non-human leucocyte antigen (HLA) susceptibility loci, imputed amino acids at HLA-DRB1 (11, 71 and 74), HLA-DPB1 (position 9) HLA-B (position 9) and gender. The wGRS was tested in 11 366 RA cases and 15 489 healthy controls. The risk of developing RA was estimated using logistic regression by dividing the wGRS into quintiles. The ability of the wGRS to discriminate between cases and controls was assessed by receiver operator characteristic analysis and discrimination improvement tests.
  
  
  RESULTS
  Individuals in the highest risk group showed significantly increased odds of developing anti-cyclic citrullinated peptide-positive RA compared to the lowest risk group (OR 27.13, 95% CI 23.70 to 31.05). The wGRS was validated in an independent cohort that showed similar results (area under the curve 0.78, OR 18.00, 95% CI 13.67 to 23.71). Comparison of the full wGRS with a wGRS in which HLA amino acids were replaced by a HLA tag single-nucleotide polymorphism showed a significant loss of sensitivity and specificity.
  
  
  CONCLUSIONS
  Our study suggests that in RA, even when using all known genetic susceptibility variants, prediction performance remains modest; while this is insufficiently accurate for general population screening, it may prove of more use in targeted studies. Our study has also highlighted the importance of including HLA variation in risk prediction models.
authors.affiliation: Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, The University of Manchester, Manchester, UK.
authors.forename: Annie
authors.initials: A
authors.lastname: Yarwood
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Buhm
authors.initials: B
authors.lastname: Han
authors.affiliation: Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, The University of Manchester, Manchester, UK Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, The University of Manchester, Manchester, UK.
authors.forename: John
authors.initials: J
authors.lastname: Bowes
authors.affiliation: Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, The University of Manchester, Manchester, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Lunt
authors.affiliation: Division of Rheumatology, Department of Medicine, New York Presbyterian Hospital, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Dimitrios A
authors.initials: DA
authors.lastname: Pappas
authors.affiliation: Department of Medicine, Albany Medical College, New York, New York, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Kremer
authors.affiliation: Department of Rheumatology, New York University Hospital for Joint Diseases, New York, New York, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Greenberg
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Plenge
authors.affiliation: Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, The University of Manchester, Manchester, UK NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academic Health Science Centre, Central Manchester Foundation Trust, Manchester, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.affiliation: Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, The University of Manchester, Manchester, UK NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academic Health Science Centre, Central Manchester Foundation Trust, Manchester, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.affiliation: Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, The University of Manchester, Manchester, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Eyre
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D015235:HLA-B Antigens / Q000235:genetics; D059868:HLA-DP beta-Chains / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D008297:Male; D010456:Peptides, Cyclic / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment / Q000379:methods*; D012737:Sex Factors
chemical_list: D015235:HLA-B Antigens; D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide
keywords: Autoimmune Diseases; Gene Polymorphism; Rheumatoid Arthritis